DESCRIPTION: (Applicant's Abstract) This Mentored Research Scientist Development award (KO1) resubmission requests 5 years of support for research and advanced research training on the genetic and biobehavioral etiology of substance use disorders, using nicotine addiction as a model system. Although a strong genetic contribution to smoking behavior has been well documented by recent studies, little is known about biobehavioral mechanisms that might mediate increased genetic risk. The overall goal of the proposed research is to identify electrophysiological trait markers of genetic susceptibility to nicotine addiction and to differentiate them from the long-term impact of smoking on brain function. This goal will be achieved through the integration of genetic and experimental psychophysiological methods. Epidemiological and behavioral research strongly implicates disinhibition (deficits of inhibitory selfregulation of behavior) as a potential mediator of susceptibility to smoking and other substance use behaviors. The proposed study will use an extended co-twin control design to delineate genetic and environmental causes of differences between smokers and nonsmokers on psychophysiological traits pertinent to disinhibition. Young adult MZ female twins and their siblings (total n=300) concordant and discordant for lifetime regular smoking will be recruited from an ongoing study of 3000 female twins and their parents. Assessments will include a diagnostic interview, questionnaires, and a battery of laboratory psychophysiological tests. The focus will be on electrophysiological traits theoretically and empirically linked to cognitive and behavioral disinhibition: ERPs elicited in classical oddball and Go-No Go tasks and prepulse inhibition of startle response (PPI). Specific aims are to identify genetically transmitted characteristics of CNS functioning indicative of increased vulnerability to nicotine addiction and to assess the long-term impact of smoking on brain function. Significantly elevated MZ compared to full sib correlations will lead to a future ROI proposal to study DZ pairs, to confirm genetic etiology. It is expected that the proposed study will advance our understanding of biobehavioral mechanisms mediating vulnerability to nicotine addiction and provide useful end phenotypes for future genetic linkage or association studies of smoking and other substance use disorders. The training component will include supervised research, formal course work and tutorials in advanced methods of genetic analysis, and lab training in experimental psychopharmacology. The acquired expertise will allow the candidate to better integrate genetic and psychophysiological approaches in order to establish a program of interdisciplinary research in the neurobehavioral genetics of addiction.